Description: This is metadata relating to an article that cannot be made open access due to the publisher copyright policy.
This article is an exception to the HEFCE Open Access policy.

Abstract: Children with Down Syndrome (DS) are at increased risk for acute myeloid leukemias
(ML-DS) characterized by mixed megakaryocytic and erythroid phenotype and by
acquired mutations in the GATA1 gene resulting in a short GATA1s isoform. The
chromosome 21 miR-125b cluster has been previously shown to cooperate with
GATA1s in transformation of fetal hematopoietic progenitors. Here we report that the
expression of miR-486-5p is increased in ML-DS compared to non-DS acute
megakaryocytic leukemias (AMKLs). MiR-486-5p is regulated by GATA1 and GATA1s
that bind to the promoter of its host gene ANK1. MiR-486-5p is highly expressed in
mouse erythroid precursors and knockdown in ML-DS cells reduced their erythroid
phenotype. Ectopic expression and knockdown of miR-486-5p in primary fetal liver
hematopoietic progenitors demonstrated that miR-486-5p cooperates with Gata1s to
enhance their self –renewal. Consistent with its activation of AKT, overexpression and
knockdown experiments showed its importance for growth and survival of human
leukemic cells. Thus miR-486-5p cooperates with GATA1s in supporting the growth and
survival and the aberrant erythroid phenotype of the megakaryocytic leukemias of DS.

Sponsorship: Research reported in this publication was supported by the National Cancer Institute of
the National Institutes of Health under award number U10CA098543 and
U10CA180886. The content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institutes of Health. The study
was also supported by Children with Cancer UK (SI), Samuel Waxman Cancer
Research Foundation NY and USA Israel Binational Science Foundation (to SI, JC),
Israel Science Foundation I-CORE program (SI and SM), Israel Science Foundation
Legacy program (SI), The Shabtai Donollo Italian-Israeli Fellowship program (EV),
Kamin program (SM), The Israel Cancer Research Foundation and the Daniel Turnberg
UK/Middle East Travel Fellowship from the Academy of Medical Sciences (L.G.), The
National Cancer Institute (CA120772), Elana Fund, Herrick Foundation, Kids Without
Cancer, and the Ring Screw Textron Chair for Pediatric Cancer Research (JT, YG and
SI). Research in the Gottgens laboratory is supported by Leukaemia and Lymphoma
Research, the MRC, BBSRC, CRUK, Leukaemia and Lymphoma Society, NIHR
Cambridge Biomedical Research Centre and core infrastructure support by the
Wellcome Trust to the Wellcome Trust and MRC Cambridge Stem Cell Institute and
CIMR. M.R.T. was supported by a Marie Curie Intra-European Fellowship (237296).
STC was supported by the American Society of Hematology Scholar Award and Alex's
Lemonade Stand Foundation Springboard Grant .
We acknowledge the Children’s Oncology Group AML Biology Committee for providing
patient samples. We thank Ravi Bhatia for miR-486 vectors and for sharing unpublished
data.